This invention relates to a new method for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts, involving compounds that compete with osteoclasts for the osteoclasts' site of activity.
Osteoclasts are multinucleated cells of up to 400 .mu.m in diameter that resorb mineralized tissue chiefly calcium carbonate and calcium phosphate in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
In the method of the present invention, aminoalkyl-substituted phenyl derivatives are administered in a pharmacologically effective amount that blocks osteoclasts from initiating bone resorption. These compounds have the general structural formula ##STR3## wherein n is an integer from 0 to 6;
Y is PA1 R.sup.3 is PA1 R.sup.4 is PA1 R.sup.5 is PA1 R.sup.1 and R.sup.2 are independently, PA1 R.sup.3 is PA1 R.sup.4 is PA1 Y is --CH.sub.2 -- or O; PA1 R.sup.1 and R.sup.2 are independently PA1 R.sup.4 is
CH.sub.2, PA2 O, PA2 SO.sub.2, PA2 CONH, PA2 --NHCO-- or ##STR4## R.sup.1 and R.sup.2 are independently hydrogen, PA2 C.sub.1-8 alkyl, PA2 heterocyclyl C.sub.0-4 alkyl, PA2 aryl C.sub.0-4 alkyl, PA2 amino C.sub.1-4 alkyl, PA2 C.sub.1-4 alkylamino C.sub.1-4 alkyl, PA2 C.sub.3-8 cycloalkyl or PA2 C.sub.1-6 dialkylamino C.sub.1-6 alkyl PA2 hydrogen, PA2 C.sub.1-6 alkyl, PA2 hydroxy C.sub.1-4 alkyl, PA2 carboxy C.sub.1-4 alkyl, PA2 C.sub.1-4 alkoxy C.sub.1-4 alkyl, PA2 aryl C.sub.0-4 alkyl, PA2 halogen, or PA2 CF.sub.3, PA2 C.sub.1-6 alkyl, PA2 aryl C.sub.0-4 alkyl, PA2 heterocyclyl C.sub.0-4 alkyl, and PA2 hydrogen, PA2 C.sub.1-6 alkyl, PA2 aryl C.sub.0-3 alkyl, or PA2 C.sub.1-6 alkylcarbonyloxymethyl, PA2 hydrogen, PA2 C.sub.1-8 alkyl, PA2 aryl C.sub.0-4 alkyl, or PA2 C.sub.3-8 cycloalkyl, PA2 hydrogen, PA2 C.sub.1-6 alkyl, PA2 hydroxy, PA2 carboxy, PA2 C.sub.1-4 alkyloxy, or PA2 halogen; and PA2 C.sub.1-6 alkyl, PA2 aryl C.sub.1-4 alkyl, PA2 heterocyclyl C.sub.1-4 alkyl, PA2 hydrogen, PA2 C.sub.1-8 alkyl, PA2 aryl C.sub.1-3 alkyl, PA2 heterocyclyl C.sub.1-3 alkyl, or PA2 C.sub.5-6 cycloalkyl, PA2 C.sub.1-6 alkyl, PA2 hydroxy, or PA2 C.sub.1-4 alkoxy; and PA2 C.sub.1-6 alkyl, PA2 aryl, PA2 aryl C.sub.1-2 alkyl, or PA2 heterocyclyl C.sub.1-4 alkyl,
wherein R.sup.1 and R.sup.2 may be unsubstituted or substituted with one or more groups chosen from R.sup.3, where
and the pharmaceutically acceptable salts thereof.
A preferred group of compounds used in the method of the present invention are those defined for the general structural formula shown below wherein: ##STR5## n is an integer from 2 to 6; Y is CH.sub.2, O, or --NHCO--;
wherein R.sup.1 and R.sup.2 may be unsubstituted or substituted with one or more groups chosen from R.sup.3, where
and the pharmaceutically acceptable salts thereof.
A more preferred group of compounds used in the method of the present invention are those defined for the general structural formula shown below ##STR6## wherein: n is an integer from 2 to 4;
wherein R.sup.1 and R.sup.2 may be unsubstituted or substituted with one or more groups chosen from
and the pharmaceutically acceptable salts thereof.
The pharmacologic activity of these compounds is useful in the treatment of mammals, including man.
The current major bone diseases of public concern are osteroporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis, which are associated with a 12% mortality rate within the first two years and 30% of the patients require nursing home care after the fracture.
All the conditions listed above would benefit from treatment with agents which inhibit bone resorption.